DESCRIPTION: Transcriptional regulation is an important mechanism used to control morphogenesis during embryonic development. Pax-3 is a paired domain transcription factor that plays an essential role in the development of a number of embryonic cell types including neural crest cells and limb muscles. Mutations in Pax-3 are responsible for the Splotch phenotype in mice and Waardenburg Syndrome in humans. Many of the defects found in Waardenburg Syndrome patients and Splotch mice arise from changes in the migration of limb muscle precursors and neural crest cells. Waardenburg Syndrome is the most common cause of hereditary deafness in humans and is associated with the impaired migration of melanocytes into the inner ear during embryonic development. The limb defects in Waardenburg Syndrome patients may also be caused by a cell migration defect. The experiments in this proposal are aimed at analyzing the role Pax-3 plays in cell migration. It is proposed that Pax-3 exerts its effects on limb cell precursor migration by regulating expression of the c-met receptor tyrosine kinase. Loss of Pax-3 function in these cells leads to the down-regulation of the c-met. It will be determined if Pax-3 is required autonomously for c-met expression in limb muscle precursors and whether expression of c-met in these precursor cells is able to rescue the limb muscle phenotype in Splotch mice. The promoter for the c-met gene will be isolated to determine if Pax-3 directly binds to regulatory sequences within it. The relationship will be analyzed between Pax-3 and another homeodomain protein, Lbx-1 that is also expressed in migrating limb muscle precursors. Finally a zinc-finger transcription factor, PIP1, has been identified that interacts specifically with Pax-3. Further studies will be undertaken to analyze the interaction between Pax-3 and PIP1.